In Parkinson's disease (PD), dopamine replacement therapies work well for the first a few years. However, in late stage PD, such therapies cause dyskinesia that is often more debilitating than PD itself. There is an urgent need to develop alternative approaches to treat motor impairment. We recently found that mice deficient for the striatum enriched adenylyl cyclase (AC) type V (AC5) display dopamine D2 receptor- independent motor control. However they are still dependent on dopamine D1 receptors. We hypothesize that over-expression of adenylyl cyclase type I (AC1) in striatal D1 receptor positive neurons will enable D1 receptor-independent motor control. We further hypothesize that double transgenic mice with both AC1 over-expression in D1 neurons and AC5 deficiency will display dopamine-independent motor control. We propose to generate these transgenic mice and test our hypotheses using dopamine antagonists, dopamine depletion and dopamine neuron lesions. We will examine motor functions using locomotor activity, akinesia test, gait analysis and rotarod. PUBLIC HEALTH RELEVANCE: We will generate transgenic mice with dopamine-independent motor control. Positive results will provide proof of principle and will guide the development of non- dopamine replacement based therapies for Parkinson's disease.